An α-carbon glycoside based on organic trifluoroborate, synthesis method and application in pharmaceutical production

Abstract

This invention provides a stereoselective synthesis based on organotrifluoroborate. C The synthesis method of β-glycosides involves using a catalyst, an organic trifluoroborate, and 3,4- O A mixture of carbonate olefins and an organic solvent was added, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. When 3,4- O Once the α-carbonate olefin sugar has completely disappeared, terminate the reaction to obtain the product. α Carbon glycosides. The catalyst Pd(MeCN)₂Cl₂ used in this invention can catalyze the generation of carbon glycoside products in high yields.

Description

Technical Field

[0001] This invention provides an organic trifluoroborate-based... α The synthesis methods of carbon glycosides belong to the field of organic synthesis technology. Background Technology

[0002] C The stereoselective synthesis of glycosides has attracted widespread attention due to their crucial role in various biological processes and pharmaceutical applications. C - Glycosides have a carbon glycosidic bond, and O Compared to glycosides, they exhibit greater enzymatic degradation stability, thus providing better pharmacokinetic properties. These unique glycosidic bonds are present in a large number of natural products and are known to modulate protein-glycan interactions, making them valuable scaffolds for drug development. Because glycosyl groups provide an easily accessible platform for introducing a wide range of functional groups, they lead to stereoselectivity. C - The development of various synthetic strategies in the field of glycosylation.

[0003] Recently, Professor Brown and Professor Qian reported the synthesis of glycosyl polymerization via nickel catalysis. C - Glycosides. These efficient methods enable the use of 3.0 equivalents of aryl iodine and [ ] under an inert atmosphere and in anhydrous THF. t [-BuLi-(Bpin)2] serves as a receptor, rapidly acquiring 2-Bpin- α - C - Glycosides. When Professor Liu used thionarthracene salt (2.0 equivalents) as the acceptor, it could be stereoselectively obtained with a yield of 54% to 91% upon heating at 90 °C. α - C - Glycosides. Previously, most reactions required strict operation under anhydrous and oxygen-free conditions, or high-temperature reactions, which were quite demanding and complex. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for using 3,4- under room temperature and open conditions. O - Carbonate olefin sugar donor and aryl trifluoroborate C - Glycosylation method, structural formula: The R is methyleneoxytert-butyldiphenylsilyl (-CH2OTBDPS), methyleneoxytert-butyldimethylsilyl (-CH2OTBS), methyleneoxypentanoyl (-CH2OPiv), methyleneoxybenzoyl (-CH2OBz), methyl (Me), or R = H; the Ar has the structural formula of a benzene ring, a heterocyclic ring, or a substituted benzene ring; the substituent of the substituted benzene ring includes any one of p-methyl, p-methoxy, and 3,5-trifluoromethyl; the heterocyclic ring is selected from two of 2-thiophene and 2-naphthalene.

[0005] The substituents of the substituted benzene ring include any one of o-methyl, m-methyl, o-methoxy, and m-methoxy substituted benzene rings.

[0006] The aforementioned α The carbon glycoside compound is selected from any one of the following:

[0007]

[0008] .

[0009] Another object of the present invention is to provide an organotrifluoroborate-based... α The method for synthesizing carbon glycosides includes the following steps: reacting a catalyst, an organic trifluoroborate, and 3,4- O - A mixture of carbonate enoic sugars was added to an organic solvent, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. When 3,4- O After the carbonate enoic acid has completely disappeared, terminate the reaction to obtain the product. α Carbon glycosides. The reaction formula is as follows:

[0010]

[0011] The structure of Ar in the sugar acceptor is a benzene ring, a heterocycle, and a substituted benzene ring, wherein the substituents of the substituted benzene ring include o-methyl, m-methyl, thiophene, etc.

[0012] The R is methyleneoxytert-butyldiphenylsilyl (-CH2OTBDPS), methyleneoxytert-butyldimethylsilyl (-CH2OTBS), methyleneoxypentanoyl (-CH2OPiv), methyleneoxybenzoyl (-CH2OBz), methyl (Me), or R = H; the Ar has the structural formula of a benzene ring, heterocycle, or substituted benzene ring.

[0013] The catalyst includes any one of PdCl2, Pd(OAc)2, White catalyst, and Pd(MeCN)2Cl2. The solvent includes any one of dichloromethane, trichloromethane, acetonitrile, toluene, and dimethyl sulfoxide.

[0014] In this patent, after condition screening, the catalyst Pd(MeCN)2Cl2 used can generate high yields. α Carbon glycosides.

[0015] The aforementioned α The carbon glycoside compound is selected from any one of the following:

[0016]

[0017] .

[0018] The advantage of this patent is that the use of organotrifluoroborate as a sugar acceptor allows for transition metal-catalyzed glycosylation reactions under mild conditions due to its unique properties (such as air and moisture stability). Furthermore, organotrifluoroborate, as an alternative to boric acid, borate esters, and organobororate esters, has been shown to improve the reactivity of nucleophiles, potentially overcoming the problems of harsh conditions and insufficient reactivity in conventional carbon glycosylation.

[0019] Another object of the present invention is to provide α Application of carbon glycoside compounds in the development of drugs that inhibit the in vitro activity of α-glucosidase.

[0020] This invention provides a fast and efficient method for synthesis α This invention enables the direct synthesis of carbon glycosides under open systems and mild conditions. α Carbon glycosides are characterized by high yield and excellent stereoselectivity.

[0021] Some of the compounds provided by this invention have good inhibitory properties. α - Glucosidase can be used for pharmaceutical purposes in the treatment of diabetes. Attached Figure Description

[0022] Figure 1 This is the hydrogen spectrum of compound 3c.

[0023] Figure 2 This is the carbon spectrum of compound 3c. Detailed Implementation

[0024] Experimental reagents

[0025] Pd(MeCN)₂Cl₂ (Jiangsu Xinnoco Catalyst Co., Ltd.), petroleum ether (boiling range 60-90 ℃, Tianjin Hengxing Chemical Reagent Manufacturing Co., Ltd.), ethyl acetate (analytical grade, Tianjin Kemeo Chemical Reagent Co., Ltd.), anhydrous sodium sulfate (analytical grade, Sinopharm Chemical Reagent Co., Ltd.), deuterated chloroform (deuterium atom content 99.8%, TMS content 0.03% V / V, 10*0.5 mL / box, ARMAR, Switzerland); NMR tubes (5mm 100 / pk 2 ST500-8, Norell, USA).

[0026] Experimental instruments

[0027] ZXZ-4 Rotary Vane Vacuum Pump (Linhai Tanshi Vacuum Equipment Co., Ltd.), DZF-6020 Vacuum Drying Oven (Shanghai Xinmiao Medical Instrument Manufacturing Co., Ltd.), SHB-IIIA Circulating Water Multipurpose Vacuum Pump (Shanghai Yukang Science and Education Instrument Equipment Co., Ltd.), CL-4 Flat Plate Magnetic Stirrer (Zhengzhou Changcheng Science and Industry Trade Co., Ltd.), EYELA SB-1100 Rotary Evaporator (Shanghai Ailang Instrument Co., Ltd.), FA2104B Analytical Balance (Shanghai Yueping Science and Technology Instrument Co., Ltd.), XRC-1 Micro Melting Point Tester (Sichuan University Scientific Instrument Factory), DF-101S Heat Collector Constant Temperature Heating Magnetic Stirrer (Gongyi Yingyu Yuhua Instrument Factory), GZX-9240MBE Digital Display Blower Drying Oven (Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory), ZF-6 Three-Purpose Ultraviolet Analyzer (Shanghai Jiapeng Technology Co., Ltd.), Ultrashied 400 MHz Plus Nuclear Magnetic Resonance Spectrometer (Bruker AG, Switzerland), API 4000 LC-MS / MS mass spectrometer (Brook Dalton GmbH, Germany).

[0028] Example 1

[0029] Catalyst, organic trifluoroborate and 3,4- O - A mixture of carbonate enoic sugars was added to an organic solvent, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. When 3,4- O After the carbonate enoic acid has completely disappeared, terminate the reaction to obtain the product. α Carbon glycosides. The catalyst Pd(MeCN)₂Cl₂ used in this invention can catalyze the formation of carbon glycoside products in high yields. The optimized experimental schemes for different catalysts, ligands, and solvents are analyzed as follows:

[0030]

[0031]

[0032] Note: All experiments used 0.10 mmol of 3,4- O- Carbonate olefins were reacted with 0.2 mmol of an organotrifluoroborate, 10 mol% of Pd catalyst, and 20 mol% of ligand in 2 mL of solvent at room temperature with stirring; yields were separated; stereoselectivity was determined by 1H NMR spectroscopy. NR = No reaction.

[0033] The technical solution of this invention involves screening and optimizing the reaction conditions. Using MeCN as the solvent, the catalysts were first screened (Entries 1-4). When PdCl2 was used as the catalyst, C - Glycoside was successfully formed with a yield of 77%, and only [amount not detected]. α Isomer (Entry 3). Further optimization using different Pd(II) catalysts revealed that Pd(MeCN)₂Cl₂ was the most effective, yielding the desired product in 94% yield (Entry 4). Subsequent changes to the ligand (Entries 5-6) resulted in moderate product yields and selectivity. Screening of six solvents (Entries 7-12) also failed to achieve yields exceeding those obtained with acetonitrile. Based on all experimental results, Entry 4 was ultimately determined as the optimal condition, using Pd(MeCN)₂Cl₂ as the catalyst and acetonitrile as the solvent, in an open system at room temperature to confirm the synthesis... α - C -Aryl glycosides.

[0034] In the case of the above-described route, the present invention uses 3,4- O Carbon glycosides were prepared using carbonate enolates and organic trifluoroborates as raw materials, and the technical route is as follows:

[0035]

[0036] (3a) R 4 R )-4-((tert-butyldiphenylsilyl)oxy)methyl)-3a,7a-dihydro-4 H -[1,3]dioxo[4,5- c Pyran-2-one (0.1 mmol, 41.1 mg), potassium trifluoro(4-methylphenyl)borate (0.2 mmol, 39.6 mg), Pd(MeCN)₂Cl₂ (0.01 mmol, 2.6 mg), and 2 mL of acetonitrile were added to a reaction flask to initiate the reaction. The reaction progress was monitored by TLC. When 3,4- O After the carbonate glycosides have completely reacted, the reaction is quenched, the organic phase is extracted and collected, the solvent is removed by vacuum distillation to obtain the crude product, and then column chromatography is performed using petroleum ether / ethyl acetate solution as the mobile phase to obtain the C-glycoside product (yield 94%). 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.61 (m, 4H), 7.43 – 7.38 (m, 2H), 7.37 – 7.32 (m, 4H), 7.29 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.29 –6.20 (m, 2H, H-3, H-2), 5.32 (d, J = 2.0 Hz, 1H, H-1), 3.92 (ddd, J = 9.3, 4.7,2.1 Hz, 1H, H-4), 3.88 – 3.81 (m, 2H, H-6), 3.71 (td, J = 6.2, 2.1 Hz, H-5),2.37 (s, 3H), 2.00 (d, J = 9.0 Hz, 1H), 1.03 (s, 9H); 13 C{ 1 H NMR (100 MHz, CDCl3) d 137.6, 136.1, 135.8, 135.7, 133.5, 133.4, 131.6, 129.8, 129.7, 129.1,127.8, 127.8, 127.7, 74.0, 72.3, 63.8, 62.5, 26.9, 21.2, 19.2; HRMS (ESI) m / z:[M + Na] + calcd for C 29 H 34 O3SiNa + 481.2169; found 481.2171; = -128.4 (c = 1.0, CHCl3).

[0037] The substrate range of C-glycosides generated by the reaction of potassium arylboronate and cyclic carbonate galactene (obtained under the conditions of Example 1):

[0038] .

[0039] The range of C-glycoside substrates for the synthesis of different types of carbonate enoses (under the conditions of Example 1) is as follows:

[0040] .

[0041] Activity evaluation

[0042] Enzymes used in the experiment α -In vitro glucosidase inhibitory activity, detection of multiple compounds on α - Inhibitory activity against glucosidase, with acarbose as the positive control. Preparation of the reaction solution: The sample and positive control are dissolved in DMSO.

[0043] α -In vitro glucosidase inhibitory activity, detection of multiple compounds on α - Inhibitory activity of glucosidase. The experiment was divided into enzyme activity group ( α - Glucosidase solution and buffer solution), enzyme blank group (buffer and sample), positive group ( α - Glucosidase solution and positive drug solution), positive blank group (buffer solution and positive drug solution), sample group ( α - Glucosidase solution and sample) and sample blank group (buffer solution and sample). For the above groups, we conducted the corresponding studies. First: Accurately weigh 1-2 mg of sample and positive control (acarbose), dissolve them separately in dimethyl sulfoxide (DMSO), and then dilute the sample solution with PBS buffer (0.1 mol / mL, pH = 6.8); Second: Accurately measure 20 mg of sample using a standard pipette. m L, 50 m L's α Add glucosidase solution (0.2 U / mL) to a 96-well plate, vortex for 2 minutes to mix completely. Then incubate at 37 °C for 10 minutes, and add 25 μL of glucosidase solution. m L substrate (PNPG) solution, shake to mix thoroughly, and incubate at 37 ℃ for half an hour; Third: Add 100 m The inhibition was terminated by adding L of Na2CO3 solution. Finally, the absorbance (OD) at 405 nm was measured, and the inhibitory activity of the sample was calculated from this value. Table 1 shows the determination results of the compounds, indicating that the obtained C-glycoside compounds possess certain inhibitory activity. α - It exhibits in vitro inhibitory activity against glucosidase and has potential anti-diabetic properties.

[0044] Table 1. Compounds α Results of in vitro inhibition activity of glucosidase

[0045]

Claims

1. α Carbon glycoside compounds, characterized in that, The aforementioned α The carbon glycoside compound is selected from any one of the following: ； 。 2. A kind α A method for synthesizing carbon glycosides, characterized in that, The steps include: under open air conditions, the catalyst, organic trifluoroborate, and 3,4- O - A mixture of carbonate enoic sugars was added to an organic solvent, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. When 3,4- O After the carbonate enoic acid has completely disappeared, terminate the reaction to obtain the product. α The reaction formula for the carbon glycoside is as follows: The 3,4- O In -carbonate enoic acid compounds, R is methyleneoxytert-butyldiphenylsilyl-CH2OTBDPS, methyleneoxytert-butyldimethylsilyl-CH2OTBS, methyleneoxytert-pentanoyl-CH2OPiv, methyleneoxybenzoyl-CH2OBz, methyl Me, or R=H; The catalyst includes any one of PdCl2, Pd(OAc)2, White catalyst, and Pd(MeCN)2Cl2; In organic trifluoroborate compounds, the structural formula of Ar is any one of a benzene ring, 2-thiophene, 2-naphthalene, or a substituted benzene ring; The substituted benzene ring is any one of o-methyl, m-methyl, o-methoxy, and m-methoxy substituted benzene rings.

3. As described in claim 2 α A method for synthesizing carbon glycosides, characterized in that, The organic solvent includes any one of dichloromethane, trichloromethane, acetonitrile, toluene, and dimethyl sulfoxide.

4. The method for synthesizing according to any one of claims 2-3 α Application of carbon glycoside compounds in the preparation of drugs that inhibit α-glucosidase activity.

5. A drug for inhibiting α-glucosidase activity, characterized in that, Including the synthesis obtained by the method of any one of claims 2-3 α Carbon glycoside compounds.

6. An antidiabetic drug, characterized in that, Including the synthesis obtained by the method of any one of claims 2-3 α Carbon glycoside compounds.

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